Over the last decade, it has become clear that cigarette smoking induces lung cancer and vascular disease. It is a major risk factor in the occurrence of heart attack and stroke. Vascular disease leads to tissue damage including heart attack and stroke and is by far the leading cause of morbidity and mortality in the United States. Tobacco use leads to tissue injury in the lungs, heart and vasculature and is implicated in approximately 20% of all deaths in the United States. Tobacco induced peripheral vascular disease results in a broad range of medical complications including vascular insufficiency, claudication, stasis ulcers, wound formation, impaired wound healing and chronic wounds.
Cigarette smoke has a very high content of free radicals, molecules with unpaired electron spin, that are highly reactive and once present in cells and tissues induce lipid, protein and DNA damage. These free radicals as well as secondary oxygen and nitrogen centered radicals are the key radical species that trigger tobacco-induced carcinogenesis, as well as cardiovascular and lung injury. Oxygen radicals can trigger an inflammatory response through leukocyte chemotaxis and activation that in turn results in a vicious cycle of further oxidant formation and inflammation. Investigators of this program have demonstrated that oxygen radicals induce cellular proliferation, a key process in the pathogenesis of cancer and atherosclerosis [5].
In just over two decades the advent of magnetic resonance imaging (MRI) has revolutionized the practice of medicine. At an ever-accelerating rate MRI has achieved breakthroughs first in enabling high-resolution anatomical imaging of tissue abnormalities in disease and more recently alterations in organ function. With the advent of molecular medicine and targeted therapeutics as well as the breakthroughs in the sequencing of the human genome, it has been realized that potentially the next even more powerful horizon for magnetic resonance imaging is in the imaging of molecular and gene expression that will enable the early detection or prevention of disease as well as facilitate the treatment and cure of existing illness.
Electron paramagnetic resonance (EPR) has advantages over proton NMR in that it is inherently over 1,000 times more sensitive on a spin basis and furthermore, for a given frequency, measurements may be performed at much lower magnetic fields enabling the use of low-cost magnet systems. Over the last several years, it has been shown that the electron spin-based technique of EPR imaging (EPRI) can provide high sensitivity and high resolution images of paramagnetic materials. For example at 1200 MHz it was shown that concentrations as low as 10 nM could be detected for a typical nitroxide spin label and this sensitivity is at least two orders of magnitude above that achievable even with ultra high-field proton MRI [1]. In addition, it was shown that high-resolution 3D images may be obtained with submillimeter resolution. In addition to direct EPR detection of paramagnetic spin probes, the hybrid EPR/NMR technique of Proton Electron Double Resonance Imaging (PEDRI) can also detect paramagnetic probes by the marked Overhauser enhancement observed in proton MRI signal seen upon irradiation of the electron spin. Enhancements of over 100 fold may be achieved. These enhancements translate into markedly improved image quality, contrast and resolution in biological tissues. With this marked enhancement, proton magnetization and image quality even at relatively low fields can exceed that of the highest field MRI systems. For example, in principle, PEDRI image quality at 0.2T could exceed that at 20 T, if indeed such an ultra high-field system could be built.
With recent technological advances, it has become possible to image these critical free radical mediators of disease using novel magnetic resonance imaging techniques. Advances in the magnetic resonance imaging techniques of in vivo Electron Paramagnetic Resonance Imaging (EPRI) and Proton Electron Double Resonance Imaging (PEDRI) have enabled the imaging of these critical mediators of disease and the redox stress they cause in living animals and most recently in man [2, 3, 6, 7]. These MR techniques along with new types of spin probes and spin traps as well as innovative nanoparticulate probes have enabled the imaging of free radicals, oxygen and nitric oxide [1, 8-13]. These breakthroughs have the potential to revolutionize the diagnosis and treatment of human disease. Beyond their diagnostic power, spin traps have great potential for the treatment of disease since they can trap or scavenge free radicals preventing radical-induced molecular and cellular damage. Free radicals, both extrinsic as from cigarette smoke, or intrinsic, from inflammatory stress, are central in the pathogenesis of human disease including: heart attack, stroke, cancer, neurodegenerative diseases, emphysema/obstructive pulmonary disease as well as the process of aging. The ability to trap and scavenge these critical mediators of disease has the potential to revolutionize current medical diagnosis and treatment and provide the long-awaited cures to a variety of the diseases that have plagued mankind.
While a great wealth of information may be obtained from the imaging of intrinsic protons, to achieve MR-based imaging of molecular and gene expression, there is a critical need for new imaging agents that may be designed or targeted to visualize specific molecular targets. There is also a need for probes that can be tagged to proteins or DNA, enabling generalized biomolecular and gene imaging. There is further a need, in addition to detecting these materials through their effects on proton relaxation, for the ability to directly detect paramagnetic materials using the MR technique of Electron Paramagnetic Resonance (EPR) or other MR techniques. Additionally, there is a need for new particulate probes that may be used to accurately determine oxygen concentration in cells.